Methods for protecting cells from amyloid toxicity and for inhibiting amyloid protein production
AssigneeThe Salk Institute for Biological Studies
InventorsDavid R. Schubert, Yuanbin Liu
Life of this patent
Estimating the term…
Abstract
In accordance with the present invention, there are provided novel methods of blocking amyloid protein toxicity in cells using polycylic compounds. Also provided are novel methods of decreasing amyloid protein production in cells and methods of inhibiting cell death. Invention methods can be used to prevent and treat a diverse class of disease conditions, known as amyloidoses, which are all related to the occurrence of amyloid protein deposits. Invention methods further provide methods of identifying compounds that can block amyloid toxicity or block the amyloid protein induced inhibition of MMT reduction.
Claims15
A method of blocking amyloid toxicity in cells selected from the group consisting of nerve cells, glial cells, pancreatic cells, islets of Langerhans cells, endothelial cells, and endocrinic cells, said method comprising contacting said cells with an effective amount of at least one polycyclic compound selected from biphenyl compounds of Structure I, wherein said structures are:
- or enantiomers, diastereomeric isomers or mixtures of any two or more thereof, or pharmaceutically acceptable salts thereof, wherein:
- L is C1-C12 alkylene, substituted alkylene, cycloalkylene, substituted cycloalkylene or substituted lactone radical;
- S, T, U and V are independently OH, halogen, alkyl or substituted alkyl,
- each X is independently H, OH, SH or NH2;
- X′ is H, SH, NH2 or OR, wherein R is H or lower alkyl, alkenyl, or alkynyl;
- Y′ is H, OH, SH, or NH2;
- and
- Z is H, OH, SH or NH2;
- provided, however, that at least one of Z and Y′ is H, or Z is absent when ring 3 is attached at the 3-position of ring 2.
A method of decreasing amyloid protein production in cells selected from the group consisting of nerve cells, glial cells, pancreatic cells, islets of Langerhans cells, endothelial cells and endocrine cells, said method comprising contacting said cells with an effective amount of least one polycyclic compound selected from biphenyl compounds of Structure I, wherein said structures are:
- or enantiomers, diastereomeric isomers or mixtures of any two or more thereof, or pharmaceutically acceptable salts thereof, wherein:
- L is C1-C12 alkylene, substituted alkylene, cycloalkylene, substituted cycloalkylene or substituted lactone radical;
- S, T, U and V are independently OH, halogen, alkyl or substituted alkyl,
- each X is independently H, OH, SH or NH2;
- X′ is H, SH, NH2 or OR, wherein R is H or lower alkyl, alkenyl, or alkynyl;
- Y′ is H, OH, SH, or NH2;
- and
- Z is H, OH, SH or NH2;
- provided, however, that at least one of Z and Y′ is H, or Z is absent when ring 3 is attached at the 3-position of ring 2.
A method of inhibiting nerve cell death, said method comprising contacting said nerve cell with an effective amount of least one polycyclic compound selected from biphenyl compounds of Structure I, wherein said structures are:
- or enantiomers, diastereomeric isomers or mixtures of any two or more thereof, or pharmaceutically acceptable salts thereof, wherein:
- L is C1-C12 alkylene, substituted alkylene, cycloalkylene, substituted cycloalkylene or substituted lactone radical;
- S, T, U and V are independently OH, halogen, alkyl or substituted alkyl,
- each X is independently H, OH, SH or NH2;
- X′ is H, SH, NH2 or OR, wherein R is H or lower alkyl, alkenyl, or alkynyl;
- Y′ is H, OH, SH, or NH2;
- and
- Z is H, OH, SH or NH2;
- provided, however, that at least one of Z and Y′ is H, or Z is absent when ring 3 is attached at the 3-position of ring 2.
A method for treating a disease condition that is etiologically linked to the formation and/or deposition of amyloid in a subject in need thereof, said method comprising administering to said subject a therapeutically effective amount of at least one polycyclic compound selected from biphenyl compounds of Structure I, wherein said structures are:
- or enantiomers, diastereomeric isomers or mixtures of any two or more thereof, or pharmaceutically acceptable salts thereof, wherein:
- L is C1-C12 alkylene, substituted alkylene, cycloalkylene, substituted cycloalkylene or substituted lactone radical;
- S, T, U and V are independently OH, halogen, alkyl or substituted alkyl,
- each X is independently H, OH, SH or NH2;
- X′ is H, SH, NH2 or OR, wherein R is H or lower alkyl, alkenyl, or alkynyl;
- Y′ is H, OH, SH, or NH2;
- and
- Z is H, OH, SH or NH2;
- provided, however, that at least one of Z and Y′ is H, or Z is absent when ring 3 is attached at the 3-position of ring 2.
A method of increasing cell viability, said method comprising contacting said cell with an effective amount of at least one polycyclic compound selected from biphenyl compounds of Structure I, wherein said structures are:
- or enantiomers, diastereomeric isomers or mixtures of any two or more thereof, or pharmaceutically acceptable salts thereof, wherein:
- L is C1-C12 alkylene, substituted alkylene, cycloalkylene, substituted cycloalkylene or substituted lactone radical;
- S, T, U and V are independently OH, halogen, alkyl or substituted alkyl,
- each X is independently H, OH, SH or NH2;
- X′ is H, SH, NH2 or OR, wherein R is H or lower alkyl, alkenyl, or alkynyl;
- Y′ is H, OH, SH, or NH2;
- and
- Z is H, OH, SH or NH2;
- provided, however, that at least one of Z and Y′ is H, or Z is absent when ring 3 is attached at the 3-position of ring 2.
A method of reducing amyloid deposits in a subject at risk thereof, said method comprising administering to said subject an effective amount of at least one polycyclic compound selected from biphenyl compounds of Structure I, wherein said structures are:
- or enantiomers, diastereomeric isomers or mixtures of any two or more thereof, or pharmaceutically acceptable salts thereof, wherein:
- L is C1-C12 alkylene, substituted alkylene, cycloalkylene, substituted cycloalkylene or substituted lactone radical;
- S, T, U and V are independently OH, halogen, alkyl or substituted alkyl,
- each X is independently H, OH, SH or NH2;
- X′ is H, SH, NH2 or OR, wherein R is H or lower alkyl, alkenyl, or alkynyl;
- Y′ is H, OH, SH, or NH2;
- and
- Z is H, OH, SH or NH2;
- provided, however, that at least one of Z and Y′ is H, or Z is absent when ring 3 is attached at the 3-position of ring 2.
Dependencies are inferred from the claim text.